1 Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.DArg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guineapigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression.2 Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-' s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-', i.v. The antitussive effects of subcutaneous codeine (25mg kg-') morphine (8.1 mg kg-') and BW443C (2.5mg kg-') were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-') and N-methylnalorphine (3.0mg kg-').3 In the multiple toe-pinch test, the antinociceptive ED5s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-', s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-' s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0mg kg-') antagonized the antinociceptive action of codeine (25mg kg-') and morphine (8.1 mg kg-'). In contrast, N-methylnalorphine (3.0mg kg-') had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine.4 At doses near to the i.v. ED50 values for the antitussive activity, morphine (1.5 mg kg-', i.v.) and codeine (10mg kg-', i.v.) caused small but significant depressions of ventilation (7.0 ± 2.3% and 16.5 ± 8.4% respectively). Higher doses of morphine (10, 30 and 60mg kg-',i.v.) caused further doserelated depression of ventilation (9.6 ± 5.3%, 22.4 ± 6.2% and 36.2 ± 9.6% respectively) whereas codeine (30 and 60 mg kg-' i.v.) caused stimulation of ventilation which was marked (191.3 ± 43.9%) at 60 mg kg-'. 5 Compound BW443C in doses of 1 or 10mgkg-',i.v. (approximately equal to, and 10 times the EDo for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60mg kg-', i.v. was there a significant decrease in minute volume (13.1 ± 6.8% and 15.9 ± 1.89% respectively). The depression of ventilation caused by either BW443C (60mg kg- ', i.v.) or morphine (60mg kg-', i.v.) was prevented by pretreatment with naloxone (3mg kg- ', i.v.) administered 15 min before morphine or BW443C. 6 These results in the guinea-pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.

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The hyperalgesic effect of substance P (SP) is usually described as presenting short latency. We now report that multiple injections of sub-threshold doses of SP into the foot pad of a hind paw of rats pre-treated with indomethacin induced a long-lasting hyperalgesia, sensitizing the paw to further challenges with small doses of SP, dopamine or prostacyclin. The sensitizing process also occurred after multiple injections of prostacyclin or prostaglandin E2. The sensitizing effect induced by SP, prostaglandin E2 or prostacyclin is inhibited by pre-treatment with the SP antagonist (D-Arg, D-Pro, D-Trp, Leu)-SP. We suggest that SP has an important role as a modulator in peripheral inflammatory pain by sensitizing nociceptors to its own action and to the action of different mediators. This sensitizing process could also be associated with chronic inflammatory pain.

Sipatrigine is a substituted pyrimidine derived from lamotrigine. It attenuates glutamate release in vitro and in vivo, probably as a result of sodium and calcium channel inhibition. It consistently reduces cortical infarct volume in rodent models of global, permanent focal, and transient focal ischemia (typically 50-60% reduction with maximum effective doses >20 mg/kg). Striatal protection was found in some studies but not others. The drug was effective also in a rat optic nerve model of white matter ischemia, providing complete neuroprotection at the highest concentration (100 mM) used. In monkeys, CNS penetration by sipatrigine was rapid and the steady state brain/plasma ratio was >40. In humans, low doses (< 2 mg/kg, then 1 mg/kg/8 h) were well tolerated. At higher doses a significant incidence of hallucinations and vomiting was observed. These adverse effects were speculated to be due to interactions with muscarinic receptors and 5-HT 3 (or sigma) receptors, respectively. Cardiovascular side effects appeared not to be a major concern. In electrophysiological studies, sipatrigine inhibited native neuronal sodium and calcium channels (including L, N, and P/Q type) and recombinant type IIA sodium and N and T type calcium channels, all with similar potency (IC 50 in the range 5-16 mM). Inhibitory potency was increased by high action potential firing frequencies and a depolarized resting voltage. These properties may account for its actions in vitro and in animal models but do not exclude possible additional actions in later stages of ischemic damage.

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